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1

Introduction to

Pharmaceutical Validation

Contents

• What is Validation?

• When is validation needed?

• Some Purposes of Validation

• Approaches to validation

• Scope of validation

• Advantages of validation

• Organization for validation

• Types of Documentation

• Validation Master Plan

• Types of Process Validation

1. Prospective validation

1. Concurrent validation

2. Retrospective validation

3. Revalidation

• Prerequisites for process validation

• Qualification

1. Design qualification

2. Installation qualification

3. Operational qualification

4. Performance qualification

• References

What is Validation?

Definition :

• Validation is the documented act of proving that any

procedure, process, equipment, material, activity or system

actually leads to the expected result.

ISO definition :

• Validation is the confirmation by examination and the

provision of objective evidence that the particular

requirements for a specific intended use are fulfilled.

What is Validation?

• According to the Food and Drug Administration (FDA), the goal of

validation is to:

“establish documented evidence which provides a high

degree of assurance that a specific process will

consistently produce a product meeting its

predetermined specifications and quality attributes.”

Method Validation :

• Method validation is the process of establishing the

performance characteristics and limitations of a method and

the identification of the influences which may change these

characteristics and to what extent. It is also the process of

verifying that a method is fit for purpose.

When is validation needed?

• Before introduction of a new method into routine use.

• Whenever the conditions change for which a method has

been validated, e.g., instrument with different characteristics

• Whenever the method is changed, and the change is outside

the original scope of the method.

Some Purposes of Validation

• To accept an individual sample as a member of a population

under study.

• To admit samples to the measurement process.

• To minimize later questions on sample authenticity.

• To provide an opportunity for resampling when needed.

Approaches to validation

• Two basic approaches:

1. Evidence obtained through testing (prospective and

concurrent validation), and

2. Analysis of accumulated (historical) data

(retrospective validation)

• Whenever possible, prospective validation is preferred.

• Retrospective validation is not applicable to sterile products

• Both prospective and concurrent validation, may include:

extensive product testing, which may involve extensive sample

testing (with the estimation of confidence limits for individual

results) and the demonstration of intra- and inter-batch

homogeneity;

simulation process trials;

challenge/worst case tests, which determine the robustness of

the process; and

control of process parameters being monitored during

normal production runs to obtain additional information on the

reliability of the process.

Scope of validation

• Validation requires an appropriate and sufficient

infrastructure including:

– organization, documentation, personnel and finances

• Involvement of management and quality assurance

personnel

• Personnel with appropriate qualifications and experience

• Extensive preparation and planning before validation is

performed

• A specific programme for validation activities in place

• Validation done in a structured way according to

documentation including procedures and protocols.

• Validation should be performed:

– for new premises, equipment, utilities and systems,

and processes and procedures;

– at periodic intervals; and

– when major changes have been made.

• Validation in accordance with written protocols.

• A written report on the outcome to be produced.

• Validation over a period of time, e.g.

– at least three consecutive batches (full production scale) to

demonstrate consistency. (Worst case situations should be

considered.)

– Demonstrate suitability for new manufacturing

formula or method

• Process, materials and equipment to prove consistent yield

of a product of the required quality

• Manufacturers to identify what validation work is needed

• Significant changes (facilities, equipment, processes) -

should be validated

• Risk assessment approach used to determine the scope and

extent of validation needed

Advantages of validation:

• During the process the knowledge of process increases

• Assures the repeatability of the process

• Assures the fluency of production

• Assures that the product is continuously according to the

marketing authorisation

• Decreases the risk of the manufacturing problems

• Decreases the expenses caused by the failures in production

• Decreases the risks of failing in GMP

• Decreases the expenses of the every day production even though

the validation itself will create expenses

Organization for Validation

• The qualification and validation work can be organized by

employing one or more of the following structures :

I. The consultant

II. The task force

III.The dedicated group.

• Ideally there should be a department in the organization. But if

it is not possible then, these alternative approaches are used

for the work.

The Consultants :

• On the commercial basis several consultants undertake the

work.

• Consultants can apply the experience gained in the other

companies.

• The persons with consultants may not be permanent

employees, they may be on contractual basis.

• There is a risk of incomplete job and extra expenses, if the

validation job is not completed by the consultants within the

bounds of time and cost.

The task force :

• The task force concepts refers to organisation structure with in

the company in which persons proficient in different fields are

drawn from different departments.

• Usually, persons are drawn from different departments.

• The departments are production, engineering , quality

assurance, research and developments.

• The head of the committee is resposible for validation work.

The dedicated group :

• In the dedicated group members from the following

departments are selected :

a. Production

b. Engineering

c. Calibration laboratory

d. Quality control laboratory

e. Maintenance

f. HVAC

g. Product development

Department interaction :

• Once the validation team has been constituted and mission

have been formalized, the team will interact with different

departments which are :

I. Research and development department

II. Engineering department,

III.Production department,

IV.Maintenance department,

V. Quality control department,

VI.Quality assurance department.

Types of Documentation

Validation Master Plan (VMP)

Validation protocols (VP)

Validation reports (VR)

Standard Operating Procedures (SOPs)

• The Validation Master Plan could consist of:

– Approval page and table of contents

– Introduction and objectives

– Facility and process description

– Personnel, planning and scheduling

– Responsibilities of committee members

– Process control aspects

– Equipment, apparatus, processes and systems to be

validated

– Acceptance criteria

– Documentation e.g. validation protocols and reports

– SOPs

– Training requirements

Protocol

• Protocol consists of :– Objectives of the validation and qualification study– Site of the study– Responsible personnel– Description of the equipment– SOPs – Standards– Criteria for the relevant products and processes

Report

• Report consists of :– Title– Objective of the study– Refer to the protocol– Details of material– Equipment– Programmes and cycles use– Details of procedure and test methods

Validation Master Plan

Principle

Validation in general requires a meticulous preparation and

careful planning of the various steps in the process. In

addition, all work involved should be carried out in a

structured way according to formally authorized standardized

working and administrative procedures.

In addition validation is characterized by:

Multidisciplinary approach:

A specific characteristic of validation work is that it requires the collaboration of

experts of various disciplines such as pharmacists, technologists, metrologists,

chemical analysts, microbiologists, engineers, experts on Q.A. validation etc..

Time constraint:

Generally validation work is submitted to rigorous time schedules. These studies are

always the last stage prior to taking new processes, facilities into routine operation.

Costs:

Validation studies are costly as they require time of highly specialized personnel and

expensive technology.

Purpose

The VMP should present an overview of the entire validation

operation, its organizational structure, its content and

planning. The core of the VMP being the list / inventory of the

items to be validated and the planning schedule.

A VMP helps management:

to know what the validation programme involves with respect

to time, people and money, and to understand the necessity

for the programme;

A VMP helps all members of the validation team:

to know their tasks and responsibilities.

A VMP helps GMP inspectors:

to understand the firm's approach to validation and the set up

an organisation of all validation activities.

DefinitionDefinition

• A Validation Master Plan is a document that summarises the

firm's overall philosophy, intentions and approach to be used

for establishing performance adequacy.

Scope

• All validation activities relating to critical technical

operations, relevant to product and process controls within a

firm should be included in a VMP. This includes qualification

of critical manufacturing and control equipment.

• It should comprise all Prospective, Concurrent, Retrospective

Validations as well as Re-validations.

• In case of large projects like the construction of a new facility,

often the best approach is to create a separate VMP. (In such

situations the VMP should be part of the total project

management.)

Format and Content

• The VMP should be a summary document and should

therefore be brief, concise and clear. It should not repeat

information documented elsewhere but refer to existing

documents such as Policy Documents, SOP's and Validation

Protocols/Reports.

• The VMP should be agreed by management.

• A VMP should contain data on the following

subjects/proposed chapters.

Introduction

• Firm's validation policy, general description of the scope of

those operations covered by the VMP, location and schedule

(including priorities).

Plant / Process / Product Description

• Provides a cross reference to other documents. A rationale for

the inclusion or exclusion of validations, for the validation

approach and the extent of validation should be included.

Organizational Structure of All Validation Activities

• Personnel responsibility for the VMP, protocols of individual

validation projects, validation work, report and document

preparation and control, approval / authorization of validation

protocols and reports in all stages of validation processes, tracking

system for reference and review, training needs in support of

validation.

Specific Process Considerations

• Under this heading specific characteristics / requirements of the

plant / process etc. that are critical for yielding a quality product and

need extra attention may be briefly outlined here.

List of Products / Processes / Systems to be Validated

• All validation activities comprised in the VMP should be summarized and

compiled in a matrix format. Such matrix should provide an overview and

contain:

All items covered by the VMP that are subject to validation describing the

extent of validation required [i.e. IQ, OQ and/or PQ]. It should include

validation of analytical techniques which are to be used in determining the

validation status of other processes or systems,

The validation approach, i.e. Prospective, Retrospective or Concurrent, the Re-

validation activities, actual status and future planning.

Key Acceptance Criteria

• statement on key acceptance criteria for the items listed under

above.

Documentation Format

• The format to be used for protocols and reports should be

described or referred to.

Required SOP's

• List of relevant SOP’s should be presented.

Planning & Scheduling

• An estimate of staffing (including training needs), equipment and

other specific requirements to complete the validation effort

should be described in the VMP. A time plan of the project with

detailed planning of subprojects. This time plan could be included

in the above mentioned matrix A VMP requires regular updating.

Change Control

• A statement of the company's commitment to controlling critical

changes to materials, facilities, equipment or processes (including

analytical techniques), should be included.

Types of Process Validation• Experimental approach

– Prospective validation

– Concurrent validation

• Analysis of historical data

– Retrospective validation

• Revalidation

– Periodic revalidation

– Revalidation after change

Prospective validation• carried out during the development stage by means of a risk

analysis of the production process, which is broken down into

individual steps.

• These are then evaluated on the basis of past experience to

determine whether they might lead to critical situations.

• Where possible critical situations are identified, the risk is

evaluated, the potential causes are investigated and assessed for

probability and extent, the trial plans are drawn up, and the

priorities set.

• The trials are then performed and evaluated, and an overall

assessment is made.

• If, at the end, the results are acceptable, the process is

satisfactory. Unsatisfactory processes must be modified and

improved until a validation exercise proves them to be

satisfactory.

• This form of validation is essential in order to limit the risk

of errors occurring on the production scale, e.g. in the

preparation of injectable products.

Concurrent validation• carried out during normal production

• This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process

• The first three production-scale batches must be monitored as comprehensively as possible.

• The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring.

• This careful monitoring of the first three production batches is sometimes regarded as prospective validation.

• Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product.

Retrospective ValidationRetrospective Validation

• Retrospective validation involves the examination of past

experience of production on the assumption that composition,

procedures, and equipment remain unchanged

• such experience and the results of in-process and final control

tests are then evaluated.

• Recorded difficulties and failures in production are analyzed to

determine the limits of process parameters.

• A trend analysis may be conducted to determine the extent to

which the process parameters are within the permissible range.

• Retrospective validation is obviously not a quality assurance

measure in itself, and should never be applied to new

processes or products. It may be considered in special

circumstances only, e.g. when validation requirements are first

introduced in a company.

• Retrospective validation may then be useful in establishing the

priorities for the validation programme. If the results of a

retrospective validation are positive, this indicates that the process is

not in need of immediate attention and may be validated in

accordance with the normal schedule.

• For tablets which have been compressed under individual pressure-

sensitive cells, and with qualified equipment, retrospective

validation is the most comprehensive test of the overall

manufacturing process of this dosage form. On the other hand, it

should not be applied in the manufacture of sterile products.

Revalidation

• Revalidation is needed to ensure that changes in the process and/or

in the process environment, whether intentional or unintentional, do

not adversely affect process characteristics and product quality.

• Revalidation may be divided into two broad categories:

• Revalidation after any change having a bearing on product

quality.

• Periodic revalidation carried out at scheduled intervals.

Revalidation after changes :

• Revalidation must be performed on introduction of any changes

affecting a manufacturing and/or standard procedure having a

bearing on the established product performance characteristics.

• Such changes may include those in starting material, packaging

material, manufacturing processes, equipment, in-process controls,

manufacturing areas, or support systems (water, steam, etc.). Every

such change requested should be reviewed by a qualified validation

group, which will decide whether it is significant enough to justify

revalidation and, if so, its extent.

• Revalidation after changes may be based on the performance of

the same tests and activities as those used during the original

validation, including tests on sub processes and on the equipment

concerned. Some typical changes which require revalidation include

the following:

• Changes in the starting material(s) :

Changes in the physical properties, such as density, viscosity,

particle size distribution, and crystal type and modification, of the

active ingredients or excipients may affect the mechanical properties

of the material; as a consequence, they may adversely affect the

process or the product.

• Changes in the packaging material :

e.g. replacing plastics by glass, may require changes in the

packaging procedure and therefore affect product stability.

• Changes in the process :

e.g. changes in mixing time, drying temperature and cooling

regime, may affect subsequent process steps and product

quality.

• Changes in equipment :

e.g. measuring instruments, may affect both the process and the product;

repair and maintenance work, such as the replacement of major equipment

components, may affect the process.

• Changes in the production area and support system :

e.g. the rearrangement of manufacturing areas and/or support systems, may

result in changes in the process. The repair and maintenance of support

systems, such as ventilation, may change the environmental conditions

and, as a consequence, revalidation/requalification may be necessary,

mainly in the manufacture of sterile products.

• Unexpected changes and deviations may be observed during self-inspection

or audit, or during the continuous trend analysis of process data.

Periodic revalidationPeriodic revalidation

• It is well known that process changes may occur gradually even if experienced

operators work correctly according to established methods. Similarly,

equipment wear may also cause gradual changes. Consequently, revalidation at

scheduled times is advisable even if no changes have been deliberately made.

• The decision to introduce periodic revalidation should be based essentially on

a review of historical data, i.e. data generated during in-process and finished

product testing after the latest validation, aimed at verifying that the process is

under control. During the review of such historical data, any trend in the data

collected should be evaluated.

• In some processes, such as sterilization, additional process testing

is required to complement the historical data. The degree of

testing required will be apparent from the original validation.

• Additionally, the following points should be checked at the time

of a scheduled revalidation:

• Have any changes in master formula and methods, batch size, etc.,

occurred? If so, has their impact on the product been assessed?

• Have calibrations been made in accordance with the established

programme and time schedule?

• Has preventive maintenance been performed in accordance

with the programme and time schedule?

• Have the standard operating procedures (SOPs) been properly

updated?

• Have the SOPs been implemented?

• Have the cleaning and hygiene programmes been carried out?

• Have any changes been made in the analytical control

methods?

Prerequisites for process validation• Before process validation can be started, manufacturing

equipment and control instruments, as well as the formulation,

must be qualified. Thus qualification is the prerequisites for

validation.

• The formulation of a pharmaceutical product should be studied

in detail and qualified at the development stage, i.e. before the

application for the marketing authorization is submitted. This

involves preformulation studies, studies on the compatibility

of active ingredients and excipients, and of final drug product

and packaging material, stability studies, etc.

• Other aspects of manufacture must be validated, including

critical services (water, air, nitrogen, power supply, etc.), and

supporting operations, such as equipment cleaning and

sanitation of premises. Proper training and motivation of

personnel are prerequisites to successful validation.

Qualification

• Qualification should be completed before process

validation is performed

• A logical, systematic process followed

• Start from the design phase of the premises, equipment,

utilities and equipment

• Major equipment and critical utilities and systems normally

require IQ, OQ and PQ

• Some equipment, utilities and systems require only IQ and

OQ as the correct operation could be considered to be a

sufficient indicator of its performance

• The equipment, utility and system should then be

maintained, monitored and calibrated according to a regular

schedule

Qualification Vs Validation

• Qualification and validation are essentially components of

the same concept

• The term qualification is normally used for equipment,

utilities and systems

• The term validation is normally used for processes

• In this sense, qualification is part of validation

Qualification stages

• There are four stages of qualification:

design qualification (DQ);

installation qualification (IQ);

operational qualification (OQ); and

performance qualification (PQ).

• All SOPs for operation, maintenance and calibration should

be prepared during qualification

• Training provided and records maintained

Design qualification: Provides documented evidence that the

design specifications were met

Installation qualification: Provides documented evidence

that the installation was complete and satisfactory

• During IQ:

– Purchase specifications, drawings, manuals, spare

parts lists and vendor details should be verified

– Control and measuring devices should be calibrated

Operational qualification:

• Provides documented evidence that utilities, systems or

equipment and all its components operate in accordance

with operational specifications

• Demonstrate satisfactory operation over the normal

operating range as well as at the limits of its operating

conditions (including worst case conditions)

• Operation controls, alarms, switches, displays and other

operational components should be tested

Performance qualification:

• Provides documented evidence that utilities, systems or

equipment and all its components can consistently perform

in accordance with the specifications under routine use

• Test results collected over a suitable period of time to

prove consistency

Requalification

• In accordance with a defined schedule

• Frequency to be determined (e.g. on the basis of factors

such as the analysis of results relating to calibration,

verification and maintenance)

• Periodic and after changes

– e.g. changes to utilities, systems, equipment;

maintenance work; and movement

• Part of change control procedure

References

1. P. P. Sharma, “Validation in Pharmaceutical Industry-

concepts, approaches & guidelines”, 1st edition, 2007

Vandana Publication House.

2. B. T. Loftus & R. A. Nash, "Pharmaceutical Process

Validation", Drugs and Pharm Sci. Series, Vol. 129, 3rd Ed.,

Marcel Dekker Inc., N.Y.

Probable questions :

1. Describe Validation Master Plan.

2. Explain the types of Process Validation

3. What is qualification? Explain the stages of qualification.

4. Which types of documentation is carried out in the

validation?

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